Despite the fact that ethanol is the most widely used drug and an important macronutrient, there is little information in women with respect to ethanol's nutritional value and its interactions with other macronutrients. This study was designed to test the hypotheses that in healthy women ethanol in moderate amounts 1) contains no "empty calories" but is a preferred fuel replacing fat CHO and protein as substrates for oxidation, 2) causes acute resistance to actions of insulin on CHO and fat metabolism and 3) causes deterioration of glucose tolerance in elderly women because they are unable to overcome the ethanol induced insulin resistance by over-secretion of insulin. We will test these hypotheses 1) by determining interaction of ethanol with the oxidation of other metabolic fuels (with indirect calorimetry); 2) by comparing effects of ethanol on insulin sensitivity (determined with euglycemic- hyperinsulinemic clamps) and on glucose tolerance (determined during IV glucose infusions) in young and elderly healthy women who drink alcohol rarely or not at all and in young and elderly women who habitually drink alcohol in moderate amounts. To explore possible mechanisms for ethanol induced insulin resistance, we will study effect of ethanol on intracellular pathways of CHO and fat metabolism. Measurements will include: in vivo rates of glucose uptake, glycolysis (both with 3-3H glucose), glycogen synthesis (glucose uptake minus glycolysis), non-oxidative glycolysis (glycolysis minus CHO oxidation), lipolysis (with 2H glycerol), fatty acid reesterification (with 2H5 glycerol and I-13C palmitate), CHO, fat and protei oxidation (with indirect calorimetry). Activities of pyruvate dehydrogenase and glycogen synthase and conc. of acetyl-CoA, CoA-SH, G-6-P, UDPG, lactate, pyruvate, glucose and citrate will b measured in muscle biopsies. To determine which effects are caused by ethanol or acetal-dehyde and which by acetate or its metabolites, we will perform all measurements during infusions wit acetate as well as with ethanol. We hope that these studies will provide important information on the nutritional impact of ethanol and on its possible contributory role to the development of atherosclerotic vascular disease and diabetes in women.